PROJECT I (Kl: CROWLEY) The developmental biology of GnRH in humans involves a complex interplay of biochemical and genetic systems all interacting over time and space. Notably, defects in GnRH neuronal ontogeny and function underlie a range of reproductive disorders which account for significant health care expenditures related to its consequent infertility. In the past cycle, strong collaborations between Project I and our Administrative and Phenotyping, Genotyping, and Bioinformatics Cores (Cores A & B), have allowed our Center to assemble a population of >1,300 patients/families with GnRH deficiency. We have successfully used this cohort to identify novel genes affecting the biology of the GnRH neurons and define patient phenotypes. This expanding database; its unique phenotypes and increasing genotypes; our global network of referring physicians and our increasing bioinformatic infrastructure provides a unique 'platform for human gene discovery' that will permit us to use state-of-the art genetic and genomic tools to augment the power, speed, and resolution of our gene discovery program. In Specific Aim 1, we will use contemporary genetic and genomic tools including endogamous populations; copy number variations and methylation pattern analysis; and whole exomic sequencing to identify novel genes underlying human isolated GnRH deficiency. Specific Aim 1 will also map the oligogenic interactions between the genes in the pathogenesis of isolated GnRH deficiency in humans. In Specific Aim 2, we will characterize the full genotypic-phenotypic spectrum of these new genes in the human and use the identified mutated regions of the genes to define their domain-specific biologic interactions. Finally, in Specific Aim 3, we will define the rotes played by these new genes causing isolated GnRH deficiency in common reproductive disorders such as hypothalamic amenorrhea (HA), delayed and precocious puberty.